The basic goal of this research is to determine the role of DNA repair in the effects of ionizing radiation on human cells and to understand better the mechanisms of that repair. Using human cells in vitro, we have observed that ionizing radiation induces a cyclic repair of DNA characterized by alternate incision and rejoining of DNA molecules, and cells in which such repair has been induced also evidence a cyclic radiosensitivity to a second dose of radiation as measured by survival. This cyclic radiosensitivity appears related to the state of DNA repair. We propose to investigate this observation in detail in cultured cell systems which have special relationships with three major effects of ionizing radiation in man: cell killing, accelerated aging and carcinogenesis. The parameters of cyclic repair will be defined and correlated to cell killing by measuring such repair in radioresistant cells, in cells at different phases of the cell cycle, in cells which have been exposed to drugs which reduce survival, and cells irradiated with alpha-particles which kills more cells per unit of absorbed energy. Correlation of DNA repair and aging will be investigated in cells which have reduced DNA repair capacity: cells from patients with the Hutchinson-Gilford Progeric syndrome of precocious aging and human cells which have aged in vitro. The repair-phase sensitivity of in vitro life shortening in rodent cells will be measured. Cyclic repair of DNA strand breaks will be compared in radiation-transformed rodent cells, SV40-transformed human cells, cells from rodent and human malgnancies and normal diploid cells. The correlation of cyclic repair of DNA and radiation-induction of transformation in rodent cells will be measured. The results of these experiments should present strong evidence as to the etiological role which DNA repair may play in the effects of radiation on man. Further, the documentation of the mechanism of cyclic repair may offer new insights into the structure and function of DNA.